Advisory Committee Chair
Mk Sewell-Loftin
Advisory Committee Members
Joel Berry
Bin Ren
Document Type
Thesis
Date of Award
2022
Degree Name by School
Master of Biomedical Engineering (MBE) School of Engineering
Abstract
Angiogenesis, or the growth of new vasculature from existing blood vessels, is widely considered a primary hallmark of cancer progression. When a tumor is small, diffusion is sufficient to receive essential nutrients; however, as the tumor grows a vascular supply is needed to deliver oxygen and nutrients into the increasing mass. Several anti-angiogenic cancer therapies target VEGF and its receptor VEGFR-2, which are major promoters of blood vessel development. Unfortunately, many of these cancer treatments fail to completely stop angiogenesis in the tumor microenvironment (TME). Since these therapies focus on the biochemical activation of VEGFR-2 via VEGF ligand binding, we propose that mechanical cues, particularly those found in the TME, may be a source of VEGFR-2 activation that promotes growth of blood vessel networks even in the presence of VEGF and VEGFR-2 inhibitors. In this project, we analyzed phosphorylation patterns of VEGFR-2, particularly at Y1054/Y1059 and Y1214 through either VEGF or biomechanical stimulation. Our results show prolonged and enhanced activation at the Y1214 residue when endothelial cells were stimulated with ether strain or strain and VEGF. We also analyzed the expression and activation of YAP, p38, and Src, all of which are downstream of VEGFR-2. Trends show increased activation of these pathways in ECs under strain or in the presence of VEGF. Finally, we used fibrin gels and microfluidic devices as 3D tissue mimics to simulate the TME. Magnetic beads were iii incorporated into the gels and placed above a rotating magnet, which resulted in a mechanically-active TME model. We determined that regions of mechanical strain promoted increased blood vessel growth, even in the presence of SU5416. Overall, understanding both the effects that biomechanical and biochemical stimuli have on VEGFR-2 activation and angiogenesis is an important factor in order to develop effective anti-angiogenic therapies. This project shows that VEGFR-2 can be mechanically activated through strain, and this strain likely results in increased angiogenesis in the TME.
Recommended Citation
Miller, Bronte, "The Role ofBiomechanics in Vascular Endothelial Growth Factor Receptor-2 Signaling" (2022). All ETDs from UAB. 575.
https://digitalcommons.library.uab.edu/etd-collection/575